Preclinical Development of Novel Dual OXR/KOR Antagonists for Treatment of Substance Use Disorder

用于治疗药物滥用障碍的新型双 OXR/KOR 拮抗剂的临床前开发

• 批准号: 10400321
• 负责人: John A Butera
• 金额: $ 559.85万
• 依托单位: HAGER BIOSCIENCES, LLC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2024-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10400321
• 关键词: ABCB1 gene; Acute; Address; Affect; Affinity; Animal Model; Anxiety; Arousal; Attenuated; Behavior; Behavioral Model; Binding; Binding Proteins; Biological; Biological Availability; Biological Sciences; Brain; Cessation of life; Chemicals; Clinical; Clinical Trials; Cocaine; Cocaine Abuse; Cocaine Dependence; Depressive disorder; Development; Disease; Dose; Dynorphins; Economic Burden; Emotional; FDA approved; Fentanyl; Funding; G-Protein-Coupled Receptors; Generations; Goals; Healthcare; Hepatocyte; Human; Illicit Drugs; In Vitro; Intake; Lead; Legal patent; Ligands; Medical; Mental Depression; Methamphetamine; Modality; Mood Disorders; Morbidity - disease rate; National Institute of Drug Abuse; Neuropeptides; New Agents; Non-Rodent Model; Oral; Outcome; Overdose; Performance; Permeability; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phenotype; Plasma; Primates; Procedures; Process; Property; Psychological reinforcement; Public Health; Rattus; Receptor Signaling; Relapse; Reporting; Research; Rewards; Rodent; Rodent Model; Role; Safety; Self Administration; Series; Signal Pathway; Signal Transduction; Sleep; Sleep Disorders; Sleep Wake Cycle; Sleeplessness; Solubility; Stimulus; Stress; Structure; Substance Use Disorder; Substance Withdrawal Syndrome; Substance abuse problem; Therapeutic; Treatment Efficacy; addiction; attenuation; candidate selection; chemical property; circadian; clinical candidate; clinical development; cocaine use; comparative; cost; design; dopamine system; drug market; drug of abuse; drug seeking behavior; efficacy study; fentanyl abuse; global health; health economics; hypocretin; in vivo; in vivo Model; innovation; interest; kappa opioid receptors; lead optimization; methamphetamine abuse; mortality; motivated behavior; novel; novel therapeutics; opioid use disorder; orexin 1 receptor; pharmacokinetics and pharmacodynamics; physical property; pre-clinical; preclinical development; preclinical study; prescription opioid; productivity loss; psychostimulant; public health relevance; receptor; respiratory; response; risk mitigation; safety study; scaffold; scale up; small molecule; small molecule libraries; socioeconomics; stimulant abuse; substance use; substance use treatment; tool

ABSTRACT (Project Summary) Substance use disorder (SUD) characterized by the repeated use of an addictive substance leading to loss of intake control represents a serious public health and socio-economic burden with over 164 million people affected worldwide. SUD-related costs in the US surpass $750 billion USD annually, with over $272 billion of that attributed to the abuse of illicit drugs and prescription opioids. Of these, cocaine and related stimulants cause some of the most serious morbidity. More than 20% of fatal drug overdoses (2018) in the US involved cocaine, representing over 14,666 deaths. Mortality from cocaine use disorder (CUD) has tripled in the US from 2012 to 2018. Nonetheless, there are currently no approved drugs for the treatment of CUD, making it a serious global health threat and unmet medical need. Orexin neuropeptides (OX-A and OX-B) are endogenous ligands for two GPCRs, OX1R and OX2R. Their role in sleep/wake cycle and arousal has been studied, and the use of OXR antagonists for insomnia has been clinically validated with marketed drugs for sleep disorders (i.e.: Suvorexant). In addition to circadian cycle modulation, orexins also exert their effects through actions on the mesocorticolimbic dopamine (DA) system and thus are intricately involved with motivated behavior, arousal and reward-seeking, key components of addiction behavior. While both OX1R and OX2R signaling are implicated in the sleep/arousal effects, most or all the attenuation of stress-adaptive responses and addiction/reward-seeking behavior is attributed to OX1R signaling. First generation OXR antagonists (Suvorexant) are dual-acting (DORAs), inhibiting both OX1R and OX2R with similar potencies. Recently reported OX1R antagonist tool compounds tend to be modestly selective for OX1R (~50-fold) but possess poor physical properties. Designing ligands that can modulate two or more orthogonal signaling pathways simultaneously could provide a synergistic biological response in complicated disease states like stress-related mood disorders including depression, anxiety, and SUD. As such, the goal of this application is to develop a series of first-in-class, potent / highly selective OX1R antagonists (SORAs) as Dual-Targeted Ligands which also modulate other targets - that would provide an innovative treatment for CUD without the sleep-inducing liabilities seen with existing DORAs. We have already discovered, and patented potent multi-targeted preclinical small molecule leads with the following profiles: i) Highly Selective (>1000-fold) OX1R antagonists with dual mechanism of action and ii) OX1R-prefering antagonists which also modulate other targets. Thus, the 1st Specific Aim of this U01 application is to conduct in vitro pharm profiling studies of 6 selected OX1R- Dual Targeted leads including microsomal stability, solubility, Caco-2 permeability, MDR1-MDCK efflux ratio, and plasma & brain protein binding, initiate a med chem multi-parameter lead optimization campaign; select of up to 6 lead compounds that emerge with optimal overall profiles for in vivo PK/PD studies. The 2nd Specific Aim is Assess of up to 2-4 emerging compounds with optimal pharmacology and PK/PD profiles in 2 rodent behavioral models relevant for CUD/SUD. The 3rd Specific Aim is to identify up to 2 leads and a structurally distinct backup compound which meet pre-defined metrics and perform comprehensive preclinical studies including CYP Induction, Met ID, transporters Inhibition, CYP Phenotyping, PXR activation, and human hepatocyte stability, initiate non-GMP scale-ups (50 – 200 g) of up to 2 NCEs for dose range-finding studies to support rat PK/PD. The 4th Specific Aim: is to identify and select a lead with the best overall profile to be declared as a Clinical Development Candidate(s) and start all IND-enabling studies.

摘要（项目摘要） 物质使用障碍（SUD）的特征是重复使用额外的物质导致摄入量流失 控制代表了严重的公共卫生和社会经济伯恩，全球有超过1.64亿人受到影响。 美国与SUD相关的成本每年超过7500亿美元，其中超过2720亿美元归因于滥用 非法药物和处方阿片类药物。其中，可卡因和相关兴奋剂会导致一些最严重的 发病率。在美国，超过20％的致命药物过量药物（2018年）涉及可卡因，代表14,666人死亡。 从2012年到2018年，美国使用可卡因使用障碍（CUD）的死亡率两倍。尽管如此，目前仍有 没有批准的药物来治疗CUD，这使其成为严重的全球健康威胁和未满足的医疗需求。 OREXIN 神经肽（OX-A和OX-B）是两个GPCR的内源配体，OX1R和OX2R。他们在睡眠/唤醒中的角色 循环和唤醒已经研究了，使用OXR拮抗剂用于失眠症已通过临床验证 销售睡眠障碍的药物（即suvorexant）。除了圆形周期调制外，奥雷蛋白还执行 它们通过对中皮质糖多巴胺（DA）系统的作用的影响，因此与 动机行为，唤醒和寻求奖励，成瘾行为的关键组成部分。而ox1r和ox2r却 在睡眠/唤醒效应中暗示信号，大多数或所有压力自适应反应的衰减和 成瘾/寻求奖励行为归因于OX1R信号传导。第一代oxr拮抗剂（suvorexant）是 双作用（多拉斯），抑制具有相似能力的OX1R和OX2R。最近报道的OX1R拮抗剂工具 对于OX1R（〜50倍）而言，化合物往往具有适度的选择性，但物理特性差。设计配体 可以调节两个或多个正交信号通路，这可以提供协同的生物学 复杂疾病状态的反应，例如与压力有关的情绪障碍，包括抑郁症，动画和SUD。 因此，该应用的目的是开发一系列一流的，潜在 /高度选择性的OX1R拮抗剂 （索拉斯）作为双重靶向的配体，也调节其他靶标 - 可以提供创新的治疗方法 对于现有多拉斯（Doras）看到的无睡眠负债的CUD。我们已经发现并获得了专利 潜在的多靶向临床前小分子铅具有以下特征：i）高度选择性（> 1000倍）OX1R 具有双重作用机理和ii）OX1R优先拮抗剂的拮抗剂也调节其他靶标。 这是该U01应用的第一个特定目的是对6个选定的OX1R-进行体外药物分析研究 双重靶向导线，包括微粒体稳定性，可溶性，CACO-2渗透性，MDR1-MDCK外排比， 以及血浆和脑蛋白结合，启动Med Chem多参数铅优化运动；选择 具有最佳的体内PK/PD研究的最佳总体特征，多达6种铅化合物。第二特定目标 评估2-4种具有最佳药理学和PK/PD轮廓的新兴化合物2啮齿动物行为 与CUD/SUD相关的模型。第三个特定目的是识别多达2条线索和一个结构上不同的备份 符合预定义指标并进行全面临床前研究的化合物，包括CYP 诱导，MET ID，转运蛋白抑制，CYP表型，PXR激活和人肝细胞稳定性， 启动非GMP量表（50-200 g）的剂量范围研究最多2 NCE，以支持大鼠PK/PD。 第四个特定目的是：识别并选择具有最佳总体概况的潜在客户，以称为临床 开发候选人并开始所有辅助研究。